This invention pertains generally to Fourier transform infrared spectrometers and to sample holders for such spectrometers.
Fourier transform infrared (FTIR) spectrometers are utilized to perform accurate and efficient identification of the chemical composition of a sample. Such spectrometers typically incorporate a Michelson interferometer having a moving mirror. The interferometer modulates the infrared beam from an infrared source to provide an output beam in which the intensity of the infrared radiation at various wavelengths is periodically varied. The output beam is focused and passed through or reflected from a sample, after which the beam is collected and focused onto a detector. The detector provides a time varying output signal which contains information concerning the wavelengths of infrared absorbance or reflectance of the sample. Fourier analysis is then performed on the output signal data to yield usable information on the chemical composition of the sample.
Conventional FTIR spectrometers include a sample chamber in which a sample is held in a position to be exposed to the infrared beam from the spectrometer. The sample which is to be analyzed may take various physical states, i.e., a liquid, solid or gas, and solid samples may have various physical characteristics. For example, a solid material to be analyzed may be in the form of a block or sheet of material (e.g., polymer plastics), in the form of powders or granulates, or in specific formed shapes (e.g., pharmaceutical tablets, pills and capsules).
The conventional manner of analyzing these various materials has been to prepare the sample so that it is in a form that can be accepted by the sample holder in the sample chamber of the FTIR spectrometer. For example, for a bulk liquid a small sample of the liquid may be transferred to a small cuvette or other container which is then mounted in the sample holder in the sample chamber. For bulky solid materials, small shavings or particles may be removed from the bulk sample, appropriately prepared (e.g., ground, pulverized, etc.) and placed in a sample holder which can then be inserted into the sample chamber. Other materials may be reduced to a powder which can be held in the sample holder or may be dissolved in a solvent which is then transferred to a cuvette or tube of an appropriate size to be mounted in the sample holder. Such conventional sample preparation techniques may not always be feasible or desirable, and specialized spectrometry equipment has been developed for specialized applications. These include probes, connected by fiber optic cables to a spectrometer, that can be inserted into a liquid, solid powder, or gas to be sampled (e.g., a flowing material where composition information is to be gathered for process control).
Another particular specialized use of spectroscopy equipment is in the pharmaceutical industry. The finished pharmaceuticals are usually in a specific shape, e.g., as pills, tablets, or caplets, some of which may be coated or printed with markings, as well as powder filled hard gel capsules and soft gel capsules having active ingredients suspended in water-free media surrounded by a soft gelatin shell. Classical wet chemistry methods and liquid and gas chromatographic techniques were traditionally used in the pharmaceutical industry to analyze the chemical composition of the finished pharmaceuticals. These methods require chemicals such as solvents, indicators, derivitizing agents, and chromatographic mobile phase solvent mixtures. The use of such chemicals requires specialized facilities and trained personnel, and involves fire and toxicity hazards. Such procedures involve not only the expense of the materials themselves but also the expense of their safe disposal after the analysis is done. For these reasons, nondestructive analysis techniques are increasingly being used for analysis of pharmaceuticals, as well as other compounds. One of the most widely used nondestructive techniques is near-infrared spectrographic analysis. The near-infrared region, generally in wavelengths from about 666 nm to 3333 nm, has been found to be particularly suitable for such nondestructive analysis because of its penetration depth into a pharmaceutical sample. Using near-infrared light, the sample can be analyzed in a reflectance mode or a transmittance mode.
The reflectance mode obtains information from the illuminated surface of the sample. The infrared light reflects from the surface of the sample and from shallow layers beneath the surface. Due to absorption and scattering, most of the information in the reflected light received by the detector is dominated by the composition of the surface layers, such as the coatings of pharmaceutical tablets. Some coating films are made with near-infrared transparent (e.g., modified cellulosic) materials such that the active substances in the tablet are readily detected in reflectance mode without much distortion. Other pharmaceutical formulations have coatings that have color additives or scattering materials, such as TiO2, talc, CaCO3, etc., that hinder the light from adequately reaching the interior of the tablets. In any event, the reflectance mode is sensitive to variations of the coating thickness and of the composition of the coating material. Further, if a tablet being analyzed is imprinted with ink, the spectral signature of the ink will be detected (which can be shown by comparing analyses of the printed and unprinted side of the tablet). A particular disadvantage of the reflectance sampling mode is that because the interior of the tablet is not readily analyzed, the overall dosage of the tablet cannot be directly quantified. Further, the repeatability of the optical reflectance measurement is affected by the angular position of any imprint pattern on the sample, which may vary from tablet to tablet. Thus, it is often desirable to transmit the near-infrared light through the tablet and analyze the transmitted light in addition to or as an alternative to reflectance measurements. Specialized spectrometry equipment, including specialized sample holders, have been developed for the analysis of pharmaceutical samples in the reflectance mode and in the transmission mode, but generally such equipment is not well suited to carry out both reflectance and transmission measurements on the same sample.
In accordance with the invention, a multifunctional infrared spectrometer system is capable of performing transmission or reflection measurements, or both, on a variety of samples, including liquids and powders as well as shaped solid samples such as pharmaceutical pills and tablets. The various samples can be tested utilizing the same spectrometer system without modification of the spectrometer and without the addition or rearrangement of sample compartments and sample holders. Preferably, the spectrometer system includes a sample position at which a sample may be mounted in a sample holder for transmission of a modulated infrared beam through the sample, while a sample may be analyzed at a second sample position using a probe connected by fiber optic cables to the spectrometer to analyze samples remote from the spectrometer, while at a third sample position a shaped solid sample such as a pharmaceutical tablet may be analyzed in reflection, transmission, or both. The spectrometer system is adapted to easily and quickly switch between sample positions under the command of the operator by simple commands without requiring the attachment or removal of auxiliary sample compartments or holders.
The multifunctional infrared spectrometer system of the invention includes a source of infrared radiation that provides a beam of infrared, an interferometer which receives the beam from the source and produces a modulated output beam, at least two spatially separated infrared detectors, optical elements transmitting the modulated output beam from the interferometer on a main beam path to a junction position, and optical elements defining a first branch beam path from the junction position to a first sample position and then to a first of the detectors, and optical elements defining a second branch beam path from the junction position to a second sample position and then to a second of the detectors. A multi-position mirror element is movable between at least two positions. In a first position of the mirror element, the beam on the main beam path is passed on the first branch beam path to the first sample position and thence to the first detector, wherein in a second position of the mirror element, the beam on the main beam path is passed on the second branch beam path to the second sample position and thence to the second detector. A third infrared detector may also be provided in the system which is separated from the other detectors, with optical elements defining a third branch beam path from the junction position to a third sample position and thence to the third detector, with the multi-position mirror element then movable to a third position in which the mirror element passes the beam on the main beam path on the third branch beam path to the third sample position and thence to the third detector. The multi-position mirror element is controlled by the operator preferably under software control to index to the desired position to direct the infrared beam to the desired sample position, thereby allowing different types of samples and different types of sample holders and sampling components to be used with the same spectrometer without modification of the spectrometer.
Preferably, one of the branch beam paths includes a sample holder which has a sample port at which a sample may be mounted in a conventional tube, film or cuvette for transmission of the infrared beam through the sample port and the sample to a detector. The sample holder also preferably has a reference port at which a reference material may be mounted for transmission measurements and a pass-through port which is completely open. The sample holder may be mounted on a carriage that can be indexed to move the sample holder from position to position such that the infrared beam may be passed through the sample port, or the reference port, or the pass-through port at the command of the operator. The sample holder may be heated and the temperature of the holder controlled to control the temperature of the sample and reference material as desired. By indexing the sample holder to a position at which the infrared beam passes unimpeded through the pass-through port, baseline calibration measurements can be made of the unimpeded beam path to the detector. By indexing the holder such that the infrared beam passes through the reference port, a reference spectra can be taken from a known material and the spectra thereby obtained compared to the known spectra of the reference material to allow calibration of the system.
A second of the branch beam paths may include a supply optical fiber cable which directs the beam to a probe tip at which the infrared may be projected onto and reflected from a sample (or transflected by transmission to a reflector and back through the sample), such as a bulk fluid. The infrared reflected or transflected from the sample material (e.g., the fluid in which the probe is immersed) is received at an inlet end of an optical fiber return cable which directs the reflected light back to a detector at the spectrometer. The spectrometer system may include a cradle unit with an open socket in which an elongated tube of the probe may be inserted when the probe is not being used. The cradle unit preferably includes a stop member with a reflecting member therein to which the probe tip is engaged when the probe is fully inserted into the receptacle of the cradle unit. A sensor is mounted to sense the presence of a probe tip adjacent to the stop member. The spectrometer can then automatically carry out a calibration measurement by directing infrared through the supply optical fiber cable to the reflecting member and directing a reflected light back through the return optical fiber cable to the detector to allow a baseline calibration to be made of the probe without a sample.
In a third of the branch beam paths the beam may be directed through the inlet of an integrating sphere and thence to the outlet of the integrating sphere through a window to impinge upon a solid sample, such as a pharmaceutical pill, held at a sample position on the window. The infrared light reflected from the sample passes back into the integrating sphere and is diffusely reflected from the walls of the sphere to a detector mounted in the integrating sphere. Another infrared detector is preferably mounted on the other side of the sample position from the window to detect infrared light transmitted through the sample. A shield is preferably mounted to engage the periphery of the sample, such as a tablet, to prevent the infrared light from passing around the periphery of the tablet into the detector. For round pills, a shield may be used which includes an adjustable iris having a circular inner periphery of adjustable diameter which can be narrowed down to engage to the outer periphery of a circular tablet and thus be utilized with circular tablets of various sizes. For calibration of the reflected light detector in the integrating sphere, a flip panel is preferably mounted between the outlet opening of the integrating sphere and the window which can be indexed between a position in which the infrared light is passed from the outlet opening to the sample to a position in which the flip panel blocks the infrared light exiting from the outlet opening. The flip panel then reflects the light diffusely back into the integrating sphere so that calibration measurements on the beam path to the integrating sphere detector may be obtained.
A further preferred feature of the invention includes a replaceable source having a source housing with a source enclosure to which a replaceable source element may be mounted. The source housing has an outward flange adapted to engage against a surface of the spectrometer enclosure and to be fixed precisely in location by a pin extending from the flange which is inserted into a slot or opening in the spectrometer enclosure. The replaceable source element includes electrical contact pads electrically connected to the source element that are mounted on the source housing in a position to be engaged with electrical contacts on the spectrometer enclosure to make electrical contact when the source housing is mounted into the enclosure. The source element can be readily replaced by an operator by removing the source housing from the enclosure, and then replacing the source housing in its precisely indexed position so that the source element itself is precisely located with respect to the optical elements in the main beam path of the spectrometer.
Further objects, features and advantages of the invention will be apparent from the following detailed description when taken in conjunction with the accompanying drawings.